Cortisol (CORT), a steroid hormone that is regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is a well-established biomarker for chronic stress and stress reactivity. HPA axis function is a cross-cutting physiological mechanism linked to individual differences in an array of psychiatric, health, and social outcomes, including childhood cognition. Childhood cognition, in turn, is itself a cross-cutting mechanism underlying individual differences in psychiatric disorders, physical health, and human capital across the lifespan. Previous research has conceptualized CORT as a response to environmental stress and disadvantage, as chronically elevated CORT is associated with low socioeconomic status (SES) and partially mediates the SES-cognition association. However, the genetic underpinnings of individual differences in CORT are poorly understood. Moreover, animal research has found that glucocorticoid responses to early stressful rearing experiences change the expression of genes involved in neural development. This suggests that CORT may also interact with genetic influences on child cognition, and may be a mechanism that underlies gene SES interactions observed in previous research. This project will examine the relations between genes, SES, CORT, and childhood cognition using both biometric and molecular genetic approaches. We will recruit a diverse sample of 700 same-sex twin pairs (50% monozygotic, total N = 1400 children) in grades 3-5 identified from public school rosters in two major metropolitan areas. Multi-method data will be collected from numerous sources, including (a) parent and child survey responses; (b) in-laboratory cognition and achievement testing; (c) cumulative individual-level educational records with school grades and performance on state-mandated achievement tests; (d) administrative data from state and federal agencies on neighborhood context and school quality; (e) in-laboratory cortisol reactivity and recovery in response to an acute psychosocial stressor; (f) repeated in-home assessments of cortisol diurnal rhythm; (g) accumulated cortisol levels in hair, and (h) salivary DNA samples, which we will genotype for polymorphisms in the biological CORT pathway. This combination of behavioral genetic, genotypic, educational, endocrine, and demographic data will allow us to (1) examine the genetic etiology of HPA axis function, as indexed by multiple measures of CORT output, using both twin and measured-gene methodologies; (2) test the genetic and environmental mechanisms by which CORT output is associated with child cognition; (3) test whether CORT, as well as genetic polymorphisms in the CORT pathway, interact with latent genetic influences on cognition, as estimated in a twin model (gene hormone and gene gene interactions). This innovative and interdisciplinary project will break new ground in understanding the etiology of individual differences in HPA axis function and its relations to socioeconomic disadvantage and cognitive development in children.